Recombinant TGF-β Protein Modules for Controlled Growth Factor Release
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for agents and methods to modulate cell signaling, particularly for TGF-β family member proteins, to regulate cellular activities such as cell growth, tissue homeostasis, ECM dynamics, cell migration, and immune modulation, as existing methods are inadequate in controlling the tight regulation of these processes.
Innovation Solution
Development of recombinant proteins and chimeric proteins comprising various protein modules from TGF-β family members, along with antibodies that can stabilize or release growth factors, allowing for modulation of their signaling activity, and the use of these proteins in pharmaceutical compositions for treating conditions like fibrosis and cancer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If recombinant proteins with modified furin cleavage sites are used, then growth factor release is prevented, but signaling modulation capability is reduced
Solution Approach 1:
The protein is divided into functional modules: a growth factor domain, a prodomain with furin cleavage site, and latency associated peptide. By segmenting the protein structure, the invention allows independent optimization of each domain's function while maintaining overall stability and controlled release mechanisms.
Solution Approach 2:
The invention modifies the furin cleavage site sequence parameters (specific amino acid residues) to create variants with different cleavage efficiencies. This allows tuning of the growth factor release kinetics and signaling modulation capability by changing the biochemical parameters of the cleavage site rather than altering the overall protein structure.
2Reliability
If growth factor signaling is tightly regulated, then cellular activities are controlled, but therapeutic effectiveness is reduced
Solution Approach 1:
The invention creates dynamic control systems where growth factor signaling can transition between latent and active states. The recombinant proteins can be stored in a stable latent form and then activated on-demand through furin cleavage, allowing the system to adapt between tight regulation and high therapeutic effectiveness based on physiological needs.
Solution Approach 2:
The growth factors are pre-loaded into recombinant protein structures with controlled release mechanisms. The proteins are prepared in advance in a stable, storage-ready latent form that can be administered and then activated in situ, combining the benefits of pre-regulation with on-demand therapeutic effectiveness.
3Reliability
If furin cleavage site mutations are introduced, then enzymatic cleavage is prevented, but protein stability is compromised
Solution Approach 1:
The invention creates composite protein structures combining the growth factor domain, prodomain with furin cleavage site, and latency associated peptide. This composite structure provides mutual support: the LAP and prodomain regions stabilize the overall protein while the furin cleavage site maintains its sequence integrity for controlled enzymatic processing when needed.
Data Source
AI summary
Provided herein are proteins, antibodies, assays and methods useful for modulating growth factor levels and/or activities. In some embodiments, such growth factors are members of the TGF-β superfamily of proteins.